Milton Tenenbein, MD University of Manitoba Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children: Acute Health Outcome Milton Tenenbein, MD University of Manitoba

Member of the ILSI North America Caffeine Systematic Review Team Disclosure Member of the ILSI North America Caffeine Systematic Review Team ILSI North America provided an honorarium and travel funds to attend this meeting. 

PECO Questions for the Acute Health Outcome For [population], is caffeine intake above [dose], compared to intakes [dose] or less, associated with adverse acute outcomes? Population* Healthy Adults Exposure > 400 mg/day > 10 g Comparator ≤ 400 mg/day ≤ 10 g Outcome Acute, nonlethal effects Death Example: For healthy adults, is caffeine intake above 400 mg/day, compared to intakes of 400 mg/day or less, associated with acute adverse outcomes? * Comparators not identified by Nawrot et al. 2003 for other populations

Characterization of Data for Acute Health Outcome Data Type Characterization Number of studies 26 included; 20 excluded Study types* Case reports and case series Populations Adults, pregnant women, adolescents Exposure Mostly self-reports with poor exposure characterization Voluntary and intentional consumption Few repeated exposures ~1/2 specifically evaluated caffeine (powder or tablet); others involved energy drinks or cola Outcome (Endpoints) Death, non-fatal effects associated with suicide attempts or high-dose related events (e.g., cardiovascular events; nausea; vomiting; seizures; hypokalemia) * Study types included only for acute endpoint on basis of rare effects

Considerations re: Fatal Doses For all drugs, published doses are not precise Data are based on observation, not on the scientific method Derived from case reports of suicide gestures where the dose history is unreliable Controlled studies are not possible These considerations also apply to establishing the adverse effect dose

Death The evidence demonstrates that in adolescents and adults, deaths occurred at doses mostly > 10g/day Most exposures were suicidal gestures Adverse effects in non-fatal cases included nausea, vomiting, and cardiovascular events Exposure characterization was poor Very low to low level of confidence in the body of evidence From manuscript: Following review of data from these six case reports involving assessment of acute toxicity in adolescents (aged 15–18 years), data support that the comparators of 10 g and 2.5 mg/kg/day for lethality and nonlethal endpoints, respectively, are acceptable. There is a very low to low level of confidence in the evidence base (Figure 11; Table 1). Confidence is limited by high risk of bias and likely publication bias; inherent to the case studies included, reports are limited to those reporting effects (and not reporting a lack of effects), as well as very low confidence in exposure estimates.

Non-fatal Effects Most non-fatal effects of caffeine occurred at doses > 400 mg/day Reporting bias due to nature of study types (case studies associated with effects) Most exposures were NOT suicidal gestures Adverse effects typically included nausea, vomiting, hypokalemia, seizure, and cardiovascular events (e.g. tachycardia, palpitations, changes in blood pressure) Exposure characterization was poor Very low to low level of confidence in the body of evidence From manuscript: Following review of data from these six case reports involving assessment of acute toxicity in adolescents (aged 15–18 years), data support that the comparators of 10 g and 2.5 mg/kg/day for lethality and nonlethal endpoints, respectively, are acceptable. There is a very low to low level of confidence in the evidence base (Figure 11; Table 1). Confidence is limited by high risk of bias and likely publication bias; inherent to the case studies included, reports are limited to those reporting effects (and not reporting a lack of effects), as well as very low confidence in exposure estimates. Following review of data from these 20 reports involving assessment of acute toxicity in adults, it was determined that the comparators of 10 g and 400 mg/day for lethality and nonlethal endpoints, respectively, are acceptable. There was a very low to low level of confidence in the evidence base. Confidence is limited by high risk of bias (likely publication bias) (Figure 11; Table 1); inherent to the case studies included, reports are limited to those reporting effects (and not reporting a lack of effects), as well as very low confidence in exposure estimates.

Evaluation of Individual Study Quality (Risk of Bias) Overall “high” risk of bias for studies in adults; few qualified studies in other populations, none in children Limited greatly by exposure characterization Q8: Unintended Q11: Other, purity +2: Definitely low +1: Probably low -1: Probably high -2: Definitely high

Factors that increased or decreased confidence in the body of evidence by endpoint No. of Studies Initial Confidence Rating Based on study type and study features (OHAT, 2015) Overall RoB Domain-based evaluation of risk of bias per the OHAT RoB tool (OHAT, 2015) Indirectness Was the study designed to evaluate the PECO? Magnitude Strength of effect (when effect observed below the comparator) Confounding Were plausible confounders that would change the observed effect accounted for? Consistency Were findings consistent in demonstrating effects or lack of effects at or below the comparator Final Confidence Rating What is the overall rating when factors that increase or decrease confidence were considered  Death 14 Very low to low ↓ ↑ Not Evaluated — ↑/- Other acute effects 18 ↑ increased confidence - no change to confidence ↓ decreased confidence

Weight of Evidence Conclusion: Acute Adults: When the weight of evidence was considered, 400 mg caffeine/day (2.5 mg/kg/day for adolescents) was not associated with acute adverse effects. Wide range of adverse effects observed across cases, with overlap Death has been associated with acute exposures of 10g or more Only a single report of death following a dose less than 10g Acute effects may be a result of rapid consumption and do not represent typical consumer behavior Pregnant Women & Children: insufficient evidence to develop a conclusion From manuscript:In summary, the SR of 26 studies provided evidence to evaluate potential acute toxicity. Following a weight of evidence review, the comparators of 10 g for lethality and 400 mg/day or 2.5 mg/kg/day for other acute effects, were determined to be acceptable for healthy adults and adolescents, respectively. There is very low to low confidence in this evidence base, due primarily to uncertainty in the estimates of exposure and to the high risk of bias. A higher level of confidence is also precluded by the inherent bias introduced by utilizing case reports (i.e., limitations to reporting of effects versus no effects). Insufficient and/or lack of data precluded conclusions related to acute toxicity for children and pregnant women.

Future Research Needs Improved exposure characterization (i.e., testing of blood concentrations)